This document summarizes research into identifying and targeting cancer stem cells (CSCs) in triple negative breast cancer (TNBC). The research indicates that the protein Id1 plays a pivotal role in driving the CSC phenotype in TNBC. Depletion of Id1 reduced proliferation, self-renewal, tumor growth, and metastasis in mouse models of TNBC. Analysis of gene expression changes from Id1 depletion identified potential novel CSC surface markers like Oxtr, Sctr, and Tmem252. The mechanism by which Id1 controls the CSC phenotype may involve the Wnt-β-catenin signaling pathway through suppression of the inhibitor Robo1. Targeting Id1 and the pathways it regulates could provide new therapeutic approaches
New definition and new theory (stem cell-microRNA Theory) of cancer-by dr.ra...Rajkumar Dhaugoda
Lecture notes on New definition and new theory (stem cell-microRNA Theory) of cancer
General concept of cancer
By Dr.Rkdhaugoda
CTGU, YICHANG CHINA-
Visiting Assistant professor ( FROM NEPAL)
2014- MAY-5th
“The data presented here and in the literature are consistent with the hypothesis that at least one cancer, retinoblastoma, can be caused by two mutations…. One of these mutations may be inherited as a result of a previous germinal mutation…. Those patients that inherit one mutation develop tumors earlier than do those who develop the nonhereditary form of the disease; in a majority of cases those who inherit a mutation develop more than one tumor.
BACKGROUND: Sequential Epstein-Barr virus (EBV)–positive B cell lymphoma to the initial diagnosis of angioimmunoblastic T cell lymphoma (AITL) is very rare, the exact mechanism and standard therapy of which is still being explored. CASE: A 50-year-old man was admitted to our hospital in January 2014 with a three-week history of enlargement of multiple lymph nodes. His initial pathological evaluation indicated AILT. The reactivation of EBV was observed during the immunosuppression therapy for AITL, accompanied by onset of subcutaneous nodules proven to be EBV-positive diffuse large B cell lymphoma (DLBCL) based on the pathological findings of rebiopsy. The patient was successfully treated with chidamide, a histone deacetylase (HDAC) inhibitor, and rituximab.
Conclusion: The sufficient surveillance for serum EBV and repeat biopsy is necessary for patients with AITL, and this treatment modality may become an active option.
Keywords: angioimmunoblastic T cell lymphoma, Epstein-Barr virus, HDAC inhibitor, non-Hodgkin lymphoma, peripheral T cell lymphoma
New definition and new theory (stem cell-microRNA Theory) of cancer-by dr.ra...Rajkumar Dhaugoda
Lecture notes on New definition and new theory (stem cell-microRNA Theory) of cancer
General concept of cancer
By Dr.Rkdhaugoda
CTGU, YICHANG CHINA-
Visiting Assistant professor ( FROM NEPAL)
2014- MAY-5th
“The data presented here and in the literature are consistent with the hypothesis that at least one cancer, retinoblastoma, can be caused by two mutations…. One of these mutations may be inherited as a result of a previous germinal mutation…. Those patients that inherit one mutation develop tumors earlier than do those who develop the nonhereditary form of the disease; in a majority of cases those who inherit a mutation develop more than one tumor.
BACKGROUND: Sequential Epstein-Barr virus (EBV)–positive B cell lymphoma to the initial diagnosis of angioimmunoblastic T cell lymphoma (AITL) is very rare, the exact mechanism and standard therapy of which is still being explored. CASE: A 50-year-old man was admitted to our hospital in January 2014 with a three-week history of enlargement of multiple lymph nodes. His initial pathological evaluation indicated AILT. The reactivation of EBV was observed during the immunosuppression therapy for AITL, accompanied by onset of subcutaneous nodules proven to be EBV-positive diffuse large B cell lymphoma (DLBCL) based on the pathological findings of rebiopsy. The patient was successfully treated with chidamide, a histone deacetylase (HDAC) inhibitor, and rituximab.
Conclusion: The sufficient surveillance for serum EBV and repeat biopsy is necessary for patients with AITL, and this treatment modality may become an active option.
Keywords: angioimmunoblastic T cell lymphoma, Epstein-Barr virus, HDAC inhibitor, non-Hodgkin lymphoma, peripheral T cell lymphoma
Carcinogenesis refers to the process by which a normal cell is transformed into a malignant cell and repeatedly divides to become a cancer
Chemicals which initiate this process is called chemical carcinogens
Chemicals which increase the effectiveness of carcinogens is called co-carcinogens
REGULATORY BACKGROUND
ROLE OF PROTO-ONCOGENES AND TUMOR SUPPRESSOR GENES
ACTIVATION OF PROTO ONCOGENES
OXIDATIVE STRESS IN CARCINOGENESIS
OECD guidelines
451- Carcinogenecity studies
453- Combined chronic toxicity/carcinogenecity
ICH guidelines
S1A- Guideline on the need for carcinogenicity studies of
pharmaceuticals
S1B- Testing for carcinogenicity of pharmaceuticals
S1C- Dose selection for carcinogenicity studies of pharmaceuticals
Présentation de Michel Pucéat réalisée durant le cours du réseau international des instituts Pasteur de "Médecine Génomique: du diagnostic à la thérapie " (17-21 octobre 2016)
John Quackenbush, PhD, a professor of biostatistics and computational biology talks about genomics, the human genome and what the study of it means for our understanding of diseases and, specifically, cancer.
Carcinogenesis refers to the process by which a normal cell is transformed into a malignant cell and repeatedly divides to become a cancer
Chemicals which initiate this process is called chemical carcinogens
Chemicals which increase the effectiveness of carcinogens is called co-carcinogens
REGULATORY BACKGROUND
ROLE OF PROTO-ONCOGENES AND TUMOR SUPPRESSOR GENES
ACTIVATION OF PROTO ONCOGENES
OXIDATIVE STRESS IN CARCINOGENESIS
OECD guidelines
451- Carcinogenecity studies
453- Combined chronic toxicity/carcinogenecity
ICH guidelines
S1A- Guideline on the need for carcinogenicity studies of
pharmaceuticals
S1B- Testing for carcinogenicity of pharmaceuticals
S1C- Dose selection for carcinogenicity studies of pharmaceuticals
Présentation de Michel Pucéat réalisée durant le cours du réseau international des instituts Pasteur de "Médecine Génomique: du diagnostic à la thérapie " (17-21 octobre 2016)
John Quackenbush, PhD, a professor of biostatistics and computational biology talks about genomics, the human genome and what the study of it means for our understanding of diseases and, specifically, cancer.
This presentation is part of MIU CE Pharmacy Program and is designed primarily for pharmacists with the following learning objectives:
1- Explain the mechanisms of action behind immune response to cancer and the application of immunotherapy in cancer treatment
2- Distinguish new and emerging immunotherapy classes and individual agents efficacy, safety to therapy in cancer treatment
3-Strategies to counsel and assist patients to overcome barriers to therapy, including Treatment side effects to improve adherence to therapy
Dr. Michael Morse from Duke University and Fight CRC’s Andi Dwyer discuss the state of the science and clinical care of Immunotherapy (IO); giving a glimpse of the contributions of the Fight CRC IO Workgroup.
The NICB (National Institute for Cellular Biotechnology) is located on the Dublin City University (DCU) campus in Dublin, Ireland. It is a leading multidisciplinary centre of translational research in fundamental and applied cellular biotechnology, molecular cell Biology, ocular diseases and biological chemistry. It includes a multidisciplinary team of Cell and Molecular Biologists, Biotechnologists, Chemists and Informatics specialists.
The NICB prioritises translational research involving collaborations with industry and with clinicians, and is committed to educating people from all backgrounds in the area of Biomedical Science.
This slideshare summarises the main research areas of the NICB, including:
Molecular basis for biopharmaceutical production by animal cells
Cancer – drug resistance, invasion and biomarkers
Tissue Engineering/Stem Cell Therapy – ocular diseases, diabetes
Using animal cells as research tools and models for disease research
Role of notch signalling in deveopment, cancer development and its detailed cancer cell line study for purpose of detailed targetted molecular therapeutics
El 3 de noviembre de 2015, la Fundación Ramón Areces organizó en su sede en Madrid (C/ Vitruvio, 5) una jornada sobre ‘El cáncer como consecuencia del envejecimiento: posibles soluciones’. Coordinado por la investigadora María Vallet Regí, del Departamento de Química Inorgánica y Bioinorgánica de la Universidad Complutense de Madrid, contó con la presencia, entre otros científicos, de Mariano Barbacid, Lodovico Balducci y Theresa Guise.
Similar to Poster_NSW Translational Breast Cancer Research Symposium 2016_Christina Konrad (20)
Mariano Barbacid-El cáncer como consecuencia del envejecimiento
Poster_NSW Translational Breast Cancer Research Symposium 2016_Christina Konrad
1. The Kinghorn Cancer Centre, Garvan Institute of Medical Research 384 Victoria Street Darlinghurst NSW 2010 Australia
Cancer Tumour Progression
Christina Konrad, Radhika Nair, Wee Teo, Kate Harvey, Daniel Roden, Eoin Dodson, Holly Holliday, Ben Elsworth, Alexander Swarbrick
The Kinghorn Cancer Centre & Cancer Research Division, Garvan Institute of Medical Research, Sydney, Australia
Deciphering the biology of Cancer Stem Cells in triple
negative breast cancer
Acknowledgements: This research is funded by the Cancer Counsel NSW
Aim
• Does Id1 mark CSCs in TNBC?
• Mechanism by which Id1 controls the CSC phenotype in TNBC
• Potential CSC surface markers and therapeutic targets for the
study of CSC biology and development of improved therapies
Cancer stem cells in TNBC
The development of targeted therapies have resulted in a
significant decrease in mortality rates for several breast cancer
types. However, the aggressive triple negative breast cancer
(TNBC) subtype lacks effective targeted treatments and thus
relies on chemo- or radiotherapy that are associated with relapse
and therapeutic resistance.
Cancer Stem Cells
A rare subpopulation of tumour cells, termed cancer stem
cells (CSCs), plays a critical role in driving tumour progression,
metastasis, drug resistance and relapse in TNBC.
An in depth understanding of the mechanisms driving the CSC
phenotype would provide better targeted therapies for TNBC
patients.
Id1 controls the CSC phenotype
Our research indicates a pivotal role of the Inhibitor of
differentiation 1 (Id1) protein in driving the CSC phenotype in
TNBC.
Depletion of Id1 in aTNBC metastatic model resulted in reduced
proliferation and self-renewal capacity in vitro, delayed primary
tumour growth and significantly impaired lung metastasis
formation in vivo.
Id1/Id3 depletion reduces self-renewal in a TNBC cell line model. (Courtesy by Dr. Wee Teo)
Self-renewal
Depletion of Id1/Id3 in a TNBC cell line model results in
decreased cell proliferation. (Courtesy by Dr. Wee Teo)
Proliferation
Depletion of Id1/Id3 suppresses spontaneous lung metastasis in mice. (Courtesy by Dr. Wee Teo)
Metastasis
Tumour growth
Id1/Id3 depletion results in delayed primary
tumour growth. (Courtesy by Dr. Wee Teo)
Id1 is deregulated in TNBC
Inhibitor of differentiation (Id) proteins are transcriptional
repressors that regulate cell differentiation and proliferation in
embryonic and tissue stem cells.
Id proteins are deregulated in many cancers.
Id proteins regulate the function of tissue specific transcription
factors by forming inactive complexes unable to bind DNA.
Id1 is expressed in oestrogen negative breast cancer, particularly
inTNBC, and is enriched in metastatic lesions (Gupta et al., 2007).
Id1isexpressedbyaminorityofcellswithinTNBCtumours(1-5%),
which may be CSCs.
Candidate targets of Id1
To elucidate the mechanism by which Id1 controls the CSC
phenotype, bioinformatic analyses were performed using
microarrayandRNA-SeqdatasetsfromtwodistinctTNBCmodels
characterized by Id1 depletion or expression.
Our results identified novel potential CSC surface markers and
showed evidence for Wnt-β-catenin pathway activation.
CSC surface markers
The inability of the current CSC markers to selectively enrich for
CSCs is a major limitation for the study of CSC biology.
RNA sequencing analysis of isolated Id1+ TNBC mouse tumour
cellsshowedupregulatedexpressionofmultiplesurfaceproteins
including Oxytocin receptor (Oxtr), Secretin receptor (Sctr), Lgr6
and Tmem252.
Oxtr, Sctr and Tmem252 are required for proliferation of TNBC
cells in vitro, thus possible therapeutic targets.
Our results identified novel potential CSC surface markers and
therapeutic targets in TNBC.
The ability of the surface proteins to selectively isolate the CSC population from
TNBC tumours is currently being tested by FACS and functional assays such as the
tumoursphere assay to test the CSC phenotype.
Mechanism of Id1 in CSC phenotype
TherelationshipbetweenId1andWnt-β-cateninsignallinginthe
CSC phenotype is currently being tested through knockdown
studies using reporter, tumoursphere and proliferation assays.
Knockdown of Wnt-β-catenin pathway inhibitors, such as
Robo1, rescued proliferation of TNBC cells depleted of Id1.
Basedonourresults,apossiblemechanismbywhichId1controls
the CSC phenotype in TNBC could be through Wnt-β-catenin
signalling by suppression of Robo1.
Id1 target genes driving the CSC phenotype are promishing
therapeutic targets for TNBC patients.
Akt
Lrp5/6
Axin
β-catenin
APC
GSK3β
Destruction
complex
Proteosomal
Degradation
Ub
Ub
Ub
β-catenin
Ub
Ub
Ub
Ub
Ub
Frizzled
β-catenin
β-catenin
LEFTCF
AxinAPC
GSK3β
Wnt
Lrp5/6 Frizzled
Id1
Robo1
Robo1
Akt
Ccnd1
c-Myc
Lef1
Axin2
Id1GFP+ cells
Id1GFP- cells
Tumor
Digestion of tumor
Id1GFP C3Ttg
mouse model
FACS
Id1+
CSC surface marker
Id1-
Id1+
Id1-
Isolation of cells positive and negative
for the putative CSC surface marker
Id1+
Id1-
Id1+
Id1- α-CSC marker
Id1-
Id1-
Id1+
Id1+
Validation of Id1 expression
Functional analyses for CSC phenotype
Id1+
Id1-
Id1+
Id1-
Id1GFP+ cells
Id1GFP- cells
Id1GFP+ cellsId1GFP- cells
RNA-Seq
Tumor
Digestion of tumor
Id1GFP C3Ttg
mouse model
Inducible
Promoter
Id1-shRNA Id3-shRNA
Constitutive
Promoter
Activator
Venus
Neo
+ Doxycycline
ConstitutiveInducible
4T1 cells
+ Dox
Microarray
+
Id1 expression system Id1 knockdown system
4T1 Id1/Id3 KD cells
- Dox
pSLIK inducible knockdown system
4T1 cells
Bioinformatic analyses
FACS
Potential CSC markers Downstream targets of Id1Mechanism of Id1
Downregulated
Robo1
Upregulated
Oxtr
Sctr
Lgr6
Downregulated
Ccnd1
c-Myc
Lef1
Axin2
Cell cycle
Cytoskeleton remodelling
Cell adhesion and migration
Chemotaxis